2-(1-piperazinyl)-4-substituted phenylquinoline derivatives, processes for the preparation thereof, and pharmaceutical composition containing the same

ABSTRACT

Compounds of the formula: ##STR1## wherein R 1  represents fluorine atom at the para position, chlorine atom at the para position, methyl group at the para position or trifluoromethyl group at the para or meta position; and R 2  represents hydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group or 3-hydroxypropyl group, provided that R 2  represents ethyl group, 2-hydroxyethyl group or 3-hydroxypropyl group when R 1  represents fluorine atom at the para position, methyl group at the para position or trifluoromethyl group at the para position, and a pharmaceutically acceptable salt therof, process for the preparation thereof, and pharmaceutical composition containing the same. The compounds and pharmaceutically acceptable salts thereof show excellent cytoprotective effect and useful for prophylaxis and treatment of peptic ulcer and inflammatory gastrointestinal diseases.

TECHNICAL FIELD

The present invention relates to novel and useful2-(1-piperazinyl)-4-substituted phenylquinoline derivatives havingcytoprotective effect, processes of the preparation thereof, and apharmaceutical composition containing the same.

BACKGROUND ART

The leading view as to etiology of peptic ulcer is that it is induced byimbalance of the aggressive factor such as hydrochloric acid or pepsinand the defensive factor such as mucosal resistance. Type 2 histamine(H₂) receptor antagonists such as cimetidine which has widely been usedfor the treatment of peptic ulcer depress the aggressive factor andthereby shows high healing effect on peptic ulcer, but on the otherhand, these agents cause decrease of gastric mucosal resistance whenadministered continuously, and it is assumed that it is one of thereasons of recurrence of ulcer. Accordingly, it is very desirable todevelop an antiulcer drug having properties well balanced in both ofdepression of the aggressive factor and increase of the defensivefactor. Besides, in the aged patients, there is comparatively frequentlyobserved the peptic ulcer with low gastric acidity, and hence, it isalso desired to develop a drug having an activity of specificallyincreasing the defensive factor.

By the way, there are known some 2-(1-piperazinyl)-4-phenylquinolinederivatives which have some pharmacological activities. These aresummarized below.

It is disclosed in U.S. Pat. No. 4,237,135 that2-(4-ethyl-1-piperazinyl)-4-phenylquinoline and salts thereof have anantireserpine activity, inhibitory effect on spontaneous locomotoractivity, and the like and are useful as an antidepressant withneuroleptic-like properties such as inhibition of central nervous systemand further that the compounds have also antitremorine activity.

It is disclosed in U.S. Pat. Nos. 3,542,785 and 3,668,207 that2-amino-4-arylquinoline derivatives including6-chloro-2-(4-methyl-1-piperazinyl)-4-phenylquinoline haveantiinflammatory and diuretic activities.

It is disclosed in Chem. Pharm. Bull., 28, 2618 (1980) that thepharmacological activities of the compounds as disclosed in the aboveU.S. Pat. Nos. 4,237,135, 3,542,785 and 3,668,207 and related compoundswere evaluated from the viewpoint of screening antidepressant havingalso neuroleptic-like properties such as inhibition of central nervoussystem. Besides, it is also reported that some of these compounds haveantitremorine activity.

The present inventors have studied as to pharmacological activities of2-(1-piperazinyl)-4-phenylquinoline derivatives, and in the studies,they have found that the compounds having a specific substituent on thephenyl ring at the 4-position have cytoprotective effect and are usefulas an antiulcer agent and a therapeutic agent for inflammatorygastrointestinal diseases, and then, the present invention has beenaccomplished.

DISCLOSURE OF THE INVENTION

The present invention provides compounds of the formula (I): ##STR2##wherein R₁ represents fluorine atom at the para position, chlorine atomat the para position, methyl group at the para position ortrifluoromethyl group at the para or meta position: and R₂ representshydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group or3-hydroxypropyl group, provided that R₂ represents ethyl group,2-hydroxyethyl group or 3-hydroxypropyl group when R₁ representsfluorine atom at the para position, methyl group at the para position ortrifluoromethyl group at the para position, and a pharmaceuticallyacceptable salt thereof, a process of the preparation of the compounds,and a pharmaceutical composition containing the compounds as an activeingredient.

The pharmaceutically acceptable salts of the compounds (I) include, forexample, inorganic acid addition salts (e.g. hydrochloride,hydrobromide, hydroiodide, sulfate, phosphate, etc.) and organic acidaddition salts (e.g. citrate, maleate, fumarate, tartrate, benzoate,lactate, methanesulfonate, etc.). The compounds (I) and salts thereofmay optionally be present in the form of a hydrate, and these hydratesare also included in the present invention.

The compounds of the present invention may be divided into the followingtwo groups in view of the pharmacological properties. The first group isthe compounds having properties well balanced in thegastro-cytoprotective effect (increase of defensive factor) andinhibitory effect on gastric acid secretion (depression of aggressivefactor). These compounds have very desirable profile as an antiulceragent. The second group is the compounds having no inhibitory effect ongastric acid secretion but having potent gastro-cytoprotective effectand hence these are particularly useful for the treatment of pepticulcer patients with low gastric acidity. By the way, the compounds ofthe present invention show comparatively weak or no antireserpineactivity.

Examples of the compounds of the first group are the following compoundsand pharmaceutically acceptable salts thereof:

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)quinoline,

2-[4-(3-hydroxypropyl)-1-piperazinyl]-4-(4-fluorophenyl)quinoline,

2-(1-piperazinyl)-4-(4-chlorophenyl)quinoline,

2-(4-ethyl-1-piperazinyl)-4-(4-chlorophenyl)quinoline,

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-methylphenyl)quinoline, and

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-trifluoromethylphenyl)quinoline.

Examples of the compounds of the second group are the followingcompounds and pharmaceutically acceptable salts thereof:

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-chlorophenyl)quinoline,

2-(1-piperazinyl)-4-(3-trifluoromethylphenyl)quinoline,

2-(4-ethyl-1-piperazinyl)-4-(3-trifluoromethylphenyl)quinoline, and

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(3-trifluoromethylphenyl)quinoline.

The compounds of the present invention can be prepared, for example, bythe following processes.

Process (a)

The compounds of the formula (I) can be prepared by reacting a compoundof the formula (II): ##STR3## wherein X represents a leaving atom orgroup, and R₁ is as defined above, with a piperazine compound of theformula (III): ##STR4## wherein R₂ is as defined above.

The leaving atom or group represented by X in the formula (II) denotesany atom or group which can leave off in the form of HX under thereaction conditions together with hydrogen atom bonded to the nitrogenatom at the 4-position of the piperazine compound (III). Examples of theleaving atom or group are a halogen atom such as chlorine or bromine, alower alkylthio group such as methylthio or ethylthio, a loweralkylsulfinyl group such as methanesulfinyl or ethanesulfinyl, a loweralkylsulfonyl group such as methanesulfonyl or ethanesulfonyl, a loweralkylsulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy,and an arylsulfonyloxy group such as benzenesulfonyloxy,p-toluenesulfonyloxy or m-nitrobenzenesulfonyloxy.

The reaction of the compound (II) and the piperazine compound (III) iscarried out in a suitable solvent or without using any solvent. Suitableexamples of the solvent are aromatic hydrocarbons (e.g. toluene,xylene), ketones (e.g. methyl ethyl ketone), ethers (e.g. dioxane,diglyme), alcohols (e.g. ethanol, isopropyl alcohol), dimethylformamide,and dimethyl sulfoxide. These solvents may be used alone or incombination of two or more thereof. The reaction is preferably carriedout in the presence of a base, but the compound (III) may be used in anexcess amount to serve as the base. Suitable examples of the base arealkali metal carbonates (e.g. sodium carbonate, potassium carbonate),alkali metal bicarbonates (e.g. sodium bicarbonate, potassiumbicarbonate), and tertiary amines (e.g. triethylamine). When thepiperazine compound (III) exists in the form of a hydrate, it can beused as it is. The reaction is usually carried out at a temperature offrom about 20° C. to about 200° C., preferably of from about 70° C. toabout 150° C.

The starting compounds (II) can be prepared, for example, according tothe process as disclosed in U.S. Pat. No. 3,668,207 or Chem. Pharm.Bull., 28, 2618 (1980).

Process (b)

The compound of the formula (I) in which R₂ is methyl group, ethylgroup, 2-hydroxyethyl group or 3-hydroxypropyl group can be prepared byreacting a compound of the formula (I'): ##STR5## wherein R₁ is asdefined above, with a compound of the formula (IV):

    R.sub.2 '--Y                                               (IV)

wherein Y represents a residue of a reactive ester of an alcohol and R₂' represents methyl group, ethyl group, 2-hydroxyethyl group or3-hydroxypropyl group.

In the formula (IV), the residue of a reactive ester of an alcoholrepresented by Y includes, for example, a halogen atom such as chlorine,bromine or iodine, a lower alkoxysulfonyloxy such as ethoxysulfonyloxy,an lower alkylsulfonyloxy such as methanesulfonyloxy orethanesulfonyloxy, an arylsulfonyloxy such as benzenesulfonyloxy,p-toluenesulfonyloxy or m-nitrobenzenesulfonyloxy.

The reaction of the compound (I') and the compound (IV) is carried outin a suitable solvent or without using any solvent. Suitable examples ofthe solvent are aromatic hydrocarbons (e.g. benzene, toluene, xylene),ketones (e.g. methyl ethyl ketone), ethers (e.g. dioxane), alcohols(e.g. methanol, ethanol, isopropyl alcohol), and dimethylformamide.These solvents may be used alone or in combination of two or morethereof. The reaction is preferably carried out in the presence of abase. Suitable examples of the base are the same as described above asto the process (a). The reaction is usually carried out at a temperatureof from about 20° C. to about 200° C., preferably of from about 50° C.to about 150° C.

Process (c)

The compound of the formula (I) in which R₂ is 2-hydroxyethyl group canbe prepared by reacting a compound of the above formula (I') withethylene oxide.

The reaction is carried out in a suitable solvent or without using anysolvent. Suitable examples of the solvent are the same as describedabove as to the process (b). The reaction temperature is usually in therange of from about 20° C. to about 200° C., preferably from about 50°C. to about 150° C. The reaction may optionally be carried out underpressure.

The starting compounds (I') used in the processes (b) and (c) can beprepared, for example, by reacting the compound (II) with piperazineaccording to the process (a). In the reaction, piperazine may be used inthe form of a hydrate.

The compounds prepared by the above processes can be isolated andpurified in a usual manner.

The compound (I) may be obtained in the form of a free base, salt orhydrate depending on the kinds of the starting compounds, reaction andtreating conditions, and the like. The salt can be converted into a freebase by treating it with a base such as an alkali metal hydroxide in ausual manner. On the other hand, the free base may be converted into asalt by treating it with various acids in a usual manner. For instance,when a compound of the formula (I) is reacted with an appropriate acidin a solvent and the reaction product is purified by recrystallizationor reprecipitation, there is obtained a salt of the compound (I). Thesolvent includes, for example, ethyl acetate, methanol, ethanol,isopropyl alcohol, water, and the like. The acid is usually used in anamount of one to about three moles to one mole of the compound (I). Thereaction temperature is usually in the range of from about 10° C. toabout 80° C.

The pharmacological activities of the compounds of the present inventionare illustrated by the following experiments, which were carried out asto the representative compounds of the present invention. Cimetidine andimipramine hydrochloride which are commercially available antiulceragent and antidepressant agent, respectively, were used as referencecompounds.

The compounds of the present invention used in the experiments are asfollows:

A: 2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)quinolinedihydrochloride,

B: 2-[4-(3-hydroxypropyl)-1-piperazinyl]-4-(4-fluorophenyl)quinolinedimaleate,

C: 2-(1-piperazinyl)-4-(4-chlorophenyl)quinoline maleate,

D: 2-(4-ethyl-1-piperazinyl)-4-(4-chlorophenyl)quinoline dimaleate,

E: 2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-methylphenyl)quinolinedimaleate,

F:2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-trifluoromethylphenyl)quinolinedimaleate,

G: 2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-chlorophenyl)quinolinedimaleate,

H: 2-(1-piperazinyl)-4-(3-trifluoromethylphenyl)quinoline dimaleate,

I: 2-(4-ethyl-1-piperazinyl)-4-(3-trifluoromethylphenyl)quinolinedimaleate, and

J:2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(3-trifluoromethylphenyl)quinolinedimaleate.

Test 1 Effect on the ulceration induced by ethanol in rats (gastriccytoprotection activity)

This test was carried out according to the method of Robert [cf.Gastroenterology, 77, 433 (1979)].

Male Wistar rats weighing 190 g to 200 g were fasted for 24 hours andthen given orally 1 ml of absolute ethanol. After 1 hour, the animalswere sacrificed under ether anesthesia, and the stomachs were removedand cut along the greater curvature. The length (mm) of each lesion inthe glandular portion was measured using a dissecting microscope (×12).The sum of the length (mm) of each lesion in a stomach was indicated asan ulcer index. The inhibitory rate was determined by comparing theulcer index in drug-treated groups with that in control group. Testcompounds were administered orally 30 minutes before the administrationof ethanol. In the control group, a vehicle (a 0.5% tragacanth solution)was administered orally. The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                 Dose     Number                                                      Test     (mg/kg,  of        Ulcer index                                                                            Inhibitory                               compound p.o.)    animals   (mm)     rate (%)                                 ______________________________________                                        Control  --       10        47.8 ± 7.6                                                                          --                                       A         5       10        31.6 ± 11.3                                                                         33.9                                              10       10         9.8 ± 2.9**                                                                        79.5                                              20       10         9.2 ± 4.1**                                                                        80.8                                     Control  --       5         71.0 ± 13.9                                                                         --                                       B        10       5         21.9 ± 12.1*                                                                        69.2                                     Control  --       5         35.7 ± 8.7                                                                          --                                       C        10       5          4.5 ± 3.7*                                                                         87.4                                     Control  --       5         45.2 ± 9.6                                                                          --                                       D        10       5          8.6 ± 4.5**                                                                        89.0                                     G        10       5         10.8 ± 6.3*                                                                         76.1                                     H        10       5          7.1 ± 1.9*                                                                         84.3                                     I        10       5         16.5 ± 3.9*                                                                         63.5                                     Control  --       5         33.7 ± 7.4                                                                          --                                       E        10       5         12.0 ± 2.3*                                                                         64.4                                     Control  --       5         52.4 ± 16.2                                                                         --                                       F        10       5          6.7 ± 1.8*                                                                         87.2                                     Control  --       5         35.7 ± 8.7                                                                          --                                       J        10       5          9.0 ± 4.2*                                                                         74.8                                     Control  --       5         31.9 ± 3.4                                                                          --                                       Cimetidine                                                                             100      5         23.9 ± 8.2                                                                          25.1                                     ______________________________________                                         *p < 0.05                                                                     **p < 0.01                                                               

As shown in Table 1, compounds A to J of the present invention showedsignificant protective effect at a dose of 10 mg/kg on theethanol-induced ulceration. On the other hand, cimetidine did notexhibit any significant protective effect even at a dose of 100 mg/kg.

Test 2 Effect on the ulceration induced by exposure to stress (restraintand water immersion) in rats

The effect evaluated by this test is considered to be fairly wellcorrelative to inhibitory effect on gastric acid secretion.

Male Wistar rats weighing about 200 g were used in groups of 5 animalseach. According to the method of Takagi et al. [cf. Japan. J.Pharmacol., 18, 9 (1968)], the animals were placed in individual cageswhich served to immobilize them therein and then immersed in a waterbath of 23° C. to a height of their breast in order to give stress.After 20 hours, the animals were taken out from the water bath andsacrificed under ether anesthesia, and the stomachs were removed. Thestomach was inflated with 13 ml of physiological saline and placed in a5% formalin solution for 5 minutes. After washing with physiologicalsaline, the stomach was cut along the greater curvature and the length(mm) of each lesion in the glandular portion was measured using adissecting microscope (×12). The sum of the length (mm) of each lesionin a stomach was indicated as an ulcer index. The inhibitory rate wasdetermined by comparing the ulcer index in drug-treated groups with thatin control group. Test compounds were administered orally 30 minutesbefore the immersion. In the control group, a vehicle (a 0.5% tragacanthsolution) was administered orally. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Test    Dose         Ulcer index Inhibitory                                   compound                                                                              (mg/kg, p.o.)                                                                              (mm)        rate (%)                                     ______________________________________                                        Control --           24.0 ± 2.6                                                                             --                                           A       10             7.4 ± 3.6**                                                                          69.2                                         Control --           19.3 ± 3.4                                                                             --                                           B       10            7.4 ± 1.2*                                                                            61.7                                         Control --           24.7 ± 3.2                                                                             --                                           C       10             8.5 ± 2.9**                                                                          65.6                                         Control --           29.1 ± 1.6                                                                             --                                           D       10            13.4 ± 2.1**                                                                          54.0                                         G       10           18.5 ± 6.9                                                                             36.4                                         Control --           38.9 ± 6.6                                                                             --                                           E       10            11.8 ± 4.6**                                                                          69.7                                         Control --           33.9 ± 3.9                                                                             --                                           F       10            19.8 ± 2.0*                                                                           41.6                                         I       10           27.1 ± 2.2                                                                             20.1                                         J       10           34.8 ± 3.9                                                                             -2.7                                         Control --           25.8 ± 2.9                                                                             --                                           H       10           24.7 ± 3.6                                                                              4.3                                         Control --           24.8 ± 3.8                                                                             --                                           Cimetidine                                                                            20           15.1 ± 2.9                                                                             39.1                                         ______________________________________                                         *p < 0.05                                                                     **p < 0.01                                                               

As shown in Table 2, compounds A to F of the present invention showedsignificant preventive effect at a dose of 10 mg/kg on thestress-induced ulceration. On the other hand, compounds G to J andcimetidine did not exhibit any significant effect at a dose of 10 mg/kgand 20 mg/kg, respectively.

Test 3 Effect on the ulceration induced by pylorus-ligation (Shay ulcer)in rats

Male Wistar rats weighing about 190 g were fasted for 48 hours beforeexperiment. The portion between pylorus and duodenum of each rat wasligated under ether anesthesia according to the method of Shay et al.[Gastroenterology, 5, 43 (1945)]. Each of the animals was then allowedto stand abstained from food and water in a cage. After 18 hours, theanimals were sacrificed under ether anesthesia, and the stomachs wereremoved and cut along the greater curvature. The state of ulceration wasmacroscopically observed and degree of ulceration was estimatedaccording to the following ulcer indices of 0 to 5:

0: no lesion

1: hemorrhage or erosion

2: one to four small ulcers of a diameter of less than 5 mm

3: five or more small ulcers, or one marked ulcer of a diameter of 5 mmor more

4: two or more marked ulcers

5: perforated ulcer

The inhibitory rate was determined by comparing the ulcer index indrug-treated groups with that in the control group. In addition, ED₅₀,i.e. the dose required to inhibit ulcer index by 50%, was determined bythe usual graphic method. Test compounds were administered orally 30minutes before the ligation. In the control group, a vehicle (a 0.5%tragacanth solution) was administered orally. The results are shown inTable 3.

                  TABLE 3                                                         ______________________________________                                                                          Inhibi-                                             Dose     Number           tory  ED.sub.50                             Test    (mg/kg,  of       Ulcer index                                                                           rate  (mg/kg,                               Compound                                                                              p.o.)    animals  (mm)    (%)   p.o.)                                 ______________________________________                                        Control --       5        3.6 ± 0.2                                                                          --                                          A        10      5        2.4 ± 0.4*                                                                         33.3                                                 20      5        2.0 ± 0.8                                                                          44.4  26.5                                           50      5        1.4 ± 0.2**                                                                        61.1                                                100      5        1.2 ± 0.2**                                                                        66.7                                        Control --       9        3.3 ± 0.4                                                                          --                                          Cimetidine                                                                             50      9        3.3 ± 0.3                                                                          0                                                   100      10       3.0 ± 0.5                                                                           9.1  253                                           200      9        1.9 ± 0.4*                                                                         42.4                                                500      5        0.8 ± 0.2**                                                                        75.8                                        ______________________________________                                         *p < 0.05                                                                     **p < 0.01                                                               

As shown in Table 3, compound A of the present invention was about 10times more potent than cimetidine in preventive effect on Shay ulcer.

Test 4 Antireserpine activity (antagonistic effect on hypothermiainduced by reserpine)

This test was carried out according to the method of Askew [cf. LifeSci., 2, 725 (1963)].

Male ddY mice weighing 22 g to 27 g were used in groups of 5 animalseach. Test compounds were administered orally to the animals, andimmediately 5 mg/kg of reserpine was injected intraperitoneally. Rectaltemperature of each mouse was measured 4 hours later with a thermistor(Shibaura Electric, BMG III-130). The inhibitory rate was determined bycomparing the fall of rectal temperature in drug-treated groups withthat in control group. In the control group, a vehicle (a 0.5%tragacanth solution) was administered orally. The results are shown inTable 4.

                  TABLE 4                                                         ______________________________________                                        Test          Dose       Inhibitory rate                                      compound      (mg/kg, p.o.)                                                                            (%)                                                  ______________________________________                                        A              50        20.6                                                               100        65.5                                                 B             100        59.4                                                 C             100        64.3                                                 D             100        45.2                                                 E             100        51.3                                                 Imipramine     10        29.5                                                 hydrochloride  30        69.3                                                               100        94.5                                                 ______________________________________                                    

As shown in Table 4, the potency of antireserpine activity of compoundsA to E of the present invention was one-third or less compared to thatof imipramine hydrochloride. Compounds F to J did not show anyantireserpine activity at a dose of 100 mg/kg.

It is evident from the results of Tests 1 to 4 that:

(1) compounds A to F show significant preventive effects on theethanol-induced and stress-induced ulcerations, and hence thesecompounds increase the defensive factor, thereby enhancing mucosalresistance, and also depress the aggressive factor (gastric acidsecretion):

(2) compounds G to J do not show any significant activity against thestress-induced ulceration at a dose of 10 mg/kg, but significantprotective activity against the ethanol-induced ulceration at the samedose, and hence these compounds do not affect the aggressive factor butincrease the defensive factor, thereby enhancing mucosal resistance: and

(3) the antireserpine activity of compounds A to J is relatively weak ordevoid.

Test 5 Acute toxicity

Male ddY mice weighing 20 g to 25 g were used in groups of 10 animalseach. Test compounds, dissolved or suspended in a 0.5% tragacanthsolution, were orally administered at a prescribed dose to the animals.The mortality was observed for 7 days after the administration.

As shown in Table 5, the death of mouse was not observed byadministration of 250 mg/kg of compound A. Therefore, it is clear thatthe toxic dose of the compound is far greater than the dose required toexhibit antiulcer activity. The toxicity of compounds B to J was as weakas that of compound A.

                  TABLE 5                                                         ______________________________________                                        Test       Dose       Number of dead animals/                                 compound   (mg/kg, p.o.)                                                                            number of used animals                                  ______________________________________                                        A          250        0/10                                                               500        2/10                                                               1000       5/10                                                    ______________________________________                                    

As is clear from the above explanation, the compounds of the formula (I)and pharmaceutically acceptable salts thereof have excellentcytoprotective effect with less toxicity, and hence, can be used as anantiulcer agent for the prophylaxis and treatment of peptic ulcer inmammals including human. The compounds of the present invention can alsobe used as a therapeutic agent for the prophylaxis and treatment ofinflammatory gastrointestinal diseases such as gastritis and duodenitis.

The compounds of the formula (I) and pharmaceutically acceptable saltsthereof can be administered by oral, parenteral or intrarectal route,preferably by oral route. The clinical dose of the compounds (I) andpharmaceutically acceptable salts thereof may vary according to thekinds of the compounds, administration routes, severity of disease, ageof patients, or the like, but is usually in the range of 0.1 to 20 mgper kg of body weight per day, preferably 0.2 to 10 mg per kg of bodyweight per day, in human. The dose may be divided and administered intwo to several times per day.

The compounds of the formula (I) and pharmaceutically acceptable saltsthereof are usually administered to patients in the form of apharmaceutical composition which contains a non-toxic and effectiveamount of the compounds. The pharmaceutical composition is usuallyprepared by admixing the active compounds (I) or their salts withconventional pharmaceutically acceptable carrier materials which areunreactive with the active compounds (I) or their salts. Suitableexamples of the carrier materials are lactose, glucose, mannitol,dextrin, cyclodextrin, starch, sucrose, magnesium aluminosilicatetetrahydrate, synthetic aluminum silicate, microcrystalline cellulose,sodium carboxymethylcellulose, hydroxypropylstarch, calciumcarboxymethylcellulose, ion exchange resin, methylcellulose, gelatin,acacia, hydroxypropylcellulose, low substituted hydroxypropylcellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,light anhydrous silicic acid, magnesium stearate, talc, tragacanth,bentonite, veegum, carboxyvinyl polymer, titanium dioxide, sorbitanfatty acid ester, sodium lauryl sulfate, cacao butter, glycerin,glycerides of saturated fatty acids, anhydrous lanolin, glycerogelatin,polysorbate, macrogol, vegetable oils, wax, propylene glycol, water, orthe like.

The pharmaceutical composition may be in the dosage form of tablets,capsules, granules, fine granules, powders, syrups, suspension,injections, suppositories, or the like. These preparations may beprepared by conventional methods. Liquid preparations may be prepared bydissolving or suspending the active compounds in water or other suitablevehicles, when used. Tablets, granules and fine granules may be coatedin a conventioanl manner. For preparing injection preparation, apharmaceutically acceptable salt of the compound of the formula (I) isdissolved in water, or it may optionally be dissolved in physiologicalsaline or glucose solution. And further pH adjusting agents andpreservatives may also optionally be added.

The pharmaceutical composition may contain as the active ingredient thecompound of the formula (I) or its pharmaceutically acceptable salt inthe ratio of 0.5% by weight or more, preferably 1 to 70% by weight,based upon the whole weight of the composition. The composition mayfurther contain one or more other therapeutically active compounds.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated by the following Examples andReference Examples, but should not be construed to be limited thereto.The identification of the compounds is carried out by elementaryanalysis, mass spectrum, IR spectrum, NMR spectrum, and the like.

EXAMPLE 1 Preparation of2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)quinolinedihydrochloride

A mixture of 16 g of 2-chloro-4-(4-fluorophenyl)quinoline and 25.4 g of1-(2-hydroxyethyl)piperazine is stirred at 130° C. for 3 hours. Aftercooling, water is added and the resulting mixture is extracted withethyl acetate. The organic layer is dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue is chromatographedon silica gel (150 g) with chloroform - methanol (100 : 1). The eluatespooled are concentrated to give an oily residue, which is treated withethanolic hydrogen chloride to afford the hydrochloride.Recrystallization from ethanol - ethyl acetate gives 16.7 g of the titlecompound, m.p. 210°-218° C.

EXAMPLE 2 Preparation of2-(4-ethyl-1-piperazinyl)-4-(4-chlorophenyl)quinoline dimaleate

A mixture of 1.36 g of 2-chloro-4-(4-chlorophenyl)quinoline and 1.7 g of1-ethylpiperazine is stirred at 130° C. for 2 hours. After cooling,water is added and the resulting mixture is extracted with ethylacetate. The organic layer is dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue is chromatographed onsilica gel (18 g) with chloroform. The first eluate is discarded, andthe subsequent eluates are pooled and concentrated. The residue istreated with a solution of maleic acid in ethyl acetate to afford themaleate. Recrystallization from water - methanol - ethyl acetate gives1.9 g of the title compound, m.p. 187°-189° C.

EXAMPLE 3

Preparation of 2-(1-piperazinyl)-4-(3-trifluoromethylphenyl)quinolinedimaleate

A mixture of 1.2 g of 2-chloro-4-(3-trifluoromethylphenyl)quinoline, 1.3g of anhydrous piperazine and 1 ml of toluene is heated under reflux for3 hours. After cooling, water is added and the resulting mixture isextracted with ethyl acetate. The organic layer is dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue ischromatographed on silica gel (10 g) with chloroform. The first eluateis discarded, and the subsequent eluates are pooled and concentrated.The residue is treated with a solution of maleic acid in ethyl acetateto afford the maleate. Recrystallization from methanol - ethyl acetategives 1.5 g of the title compound, m.p. 159-°160° C.

EXAMPLE 4 Preparation of2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)quinolinedihydrochloride

A mixture of 1.23 g of 2-(1-piperazinyl)-4-(4-fluorophenyl)quinoline,0.9 g of 2-bromoethanol and 1.1 g of potassium carbonate in 15 ml ofdimethylformamide is stirred at 100° C. for 3 hours. After cooling,ice-water is added and the resulting mixture is extracted with ethylacetate. The organic layer is dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue is treated insubstantially the same manner as in Example 1 to give 1.2 g of the titlecompound, m.p. 210°-218° C. (recrystallized from ethanol - ethylacetate).

EXAMPLE 5 Preparation of2-(4-ethyl-1-piperazinyl)-4-(4-chlorophenyl)quinoline dimaleate

A mixture of 1.41 g of 2-(1-piperazinyl)-4-(4-chlorophenyl)quinoline,0.8 g of ethyl iodide and 0.5 g of sodium carbonate in 20 ml of methylethyl ketone is refluxed with stirring for 8 hours. The reaction mixtureis concentrated under reduced pressure and water is added. The resultingmixture is extracted with ethyl acetate, and the organic layer is driedover anhydrous sodium sulfate and concentrated. The residue is treatedin substantially the same manner as in Example 2 to give 1.82 g of thetitle compound, m.p. 187°-189° C. (recrystallized from water -methanol - ethyl acetate).

EXAMPLE 6 Preparation of2-[4-(3-hydroxypropyl)-1-piperazinyl]-4-(4-fluorophenyl)quinolinedimaleate

A mixture of 1.23 g of 2-(1-piperazinyl)-4-(4-fluorophenyl)quinoline,0.42 g of sodium carbonate and 0.8 g of 3-chloropropyl alcohol in 10 mlof methyl ethyl ketone is heated under reflux for 20 hours. Aftercooling, water is added and the resulting mixture is extracted withethyl acetate. The organic layer is dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue is chromatographedon silica gel (15 g) with chloroform - methanol (100:1). The eluatespooled are concentrated to give an oily residue, which is treated with asolution of maleic acid in ethyl acetate to afford the maleate.Recrystallization from methanol - ethyl acetate gives 1.6 g of the titlecompound, m.p. 175°-177° C.

EXAMPLE 7 Preparation of2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)quinolinedihydrochloride

A mixture of 1.23 g of 2-(1-piperazinyl)-4-(4-fluorophenyl)quinoline,0.6 g of ethylene oxide and 30 ml of methanol is heated at 50° C. for 6hours in a sealed tube. The solvent is distilled off and the residue ischromatographed on silica gel (15 g) with chloroform. Thereafter,substantially the same procedures as in Example 1 are carried out togive 0.8 g of the title compound, m.p. 210-°218° C. (recrystallized fromethanol - ethyl acetate).

EXAMPLES 8 to 15

The following compounds are prepared in substantially the same manner asin Examples 1 to 7 using the corresponding starting materials andrecrystallized from the solvent designated in parentheses after theindication of melting points:

2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)quinoline dihydrochloridemonohydrate, m.p. 230°-235° C. (ethanol);

2-(1-piperazinyl)-4-(4-chlorophenyl)quinoline maleate, m.p. 185°-186° C.(water - methanol - ethyl acetate);

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-chlorophenyl)quinolinedimaleate, m.p. 178°-180° C. (water - methanol - ethyl acetate);

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-methylphenyl)quinolinedimaleate, m.p. 169°-170° C. (methanol - ethyl acetate);

2-(4-ethyl-1-piperazinyl)-4-(4-trifluoromethylphenyl)quinolinedimaleate, m.p. 182°-183° C. (water - methanol - ethyl acetate);

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-trifluoromethylphenyl)quinolinedimaleate, m.p. 174°-175° C. (water - methanol - ethyl acetate);

2-(4-ethyl-1-piperazinyl)-4-(3-trifluoromethylphenyl)quinolinedimaleate, m.p. 168°-169° C. (methanol - isopropyl alcohol); and

2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(3-trifluoromethylphenyl)quinolinedimaleate, m.p. 143°-144° C. (methanol - ethyl acetate).

The starting materials used in Examples 1 to 15 can be prepared by themethod described in the following Reference Examples.

REFERENCE EXAMPLE 1 Preparation of 4-(4-fluorophenyl)carbostyril

To a refluxed solution of 40 g of 2-(4-fluorobenzoyl)acetanilide in 300ml of ethanol, a sodium ethylate solution, prepared from 9.13 g ofsodium and 150 ml of ethanol, is added dropwise over a period of 2hours. The reaction mixture is refluxed for 20 minutes, allowed to cooland poured onto ice-water. The precipitate is collected, dried andrecrystallized from chloroform - diethyl ether to give 31.3 g of thetitle compound, m.p. 247°-248° C.

REFERENCE EXAMPLES 2 to 5

The following compounds are prepared in substantially the same manner asin Reference Example 1 using the corresponding starting materials andrecrystallized from the solvent designated in parentheses after theindication of melting points:

4-(4-chlorophenyl)carbostyril, m.p. 250°-251° C. (chloroform - diethylether);

4-(4-methylphenyl)carbostyril, m.p. 248°-249° C. (chloroform - ethylacetate);

4-(4-trifluoromethylphenyl)carbostyril, m.p. 254° C. (chloroform - ethylacetate); and

4-(3-trifluoromethylphenyl)carbostyril, m.p. 237° C. (chloroform - ethylacetate).

REFERENCE EXAMPLE 6 Preparation of 2-chloro-4-(4-fluorophenyl)quinoline

A mixture of 12 g of 4-(4-fluorophenyl)carbostyril and 50 ml ofphosphorus oxychloride is heated under reflux for 1.5 hours and thenconcentrated under reduced pressure. Ice-water is added to the residueand the resulting mixture is extracted with chloroform. The organiclayer is dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue is recrystallized from diethyl ether -ethanol to give 11.1 g of the title compound, m.p. 118° C.

REFERENCE EXAMPLES 7 to 10

The following compounds are prepared in substantially the same manner asin Reference Example 6 using the corresponding starting materials andrecrystallized from the solvent designated in parentheses after theindication of melting points;

2-chloro-4-(4-chlorophenyl)quinoline, m.p. 148° C. (chloroform -hexane);

2-chloro-4-(4-methylphenyl)quinoline, m.p. 78°-79° C. (diethyl ether -hexane);

2-chloro-4-(4-trifluoromethylphenyl)quinoline, m.p. 138°-139° C.(chloroform - hexane); and

2-chloro-4-(3-trifluoromethylphenyl)quinoline, m.p. 118°-120° C.(chloroform - hexane).

REFERENCE EXAMPLES 11 to 13

The following compounds are prepared in substantially the same manner asin Example 3 using the corresponding starting materials andrecrystallized from the solvent designated in parentheses after theindication of melting points:

2-(1-piperazinyl)-4-(4-fluorophenyl)quinoline 1/4 hydrate, m.p. 139° C.(chloroform - diethyl ether);

2-(1-piperazinyl)-4-(4-methylphenyl)quinoline dimaleate 1/4 hydrate,m.p. 168°-169° C. (methanol - ethyl acetate); and

2-(1-piperazinyl)-4-(4-trifluoromethylphenyl)quinoline dimaleate, m.p.184°-185° C. (methanol - ethyl acetate).

EXAMPLE 16

    ______________________________________                                        Tablets                                                                       ______________________________________                                        2-[4-(2-Hydroxyethyl)-1-piperazinyl]-4-                                                                10 g                                                 (4-fluorophenyl)quinoline dihydrochloride                                     Corn starch              33 g                                                 Lactose                  70 g                                                 Microcrystalline cellulose                                                                             30 g                                                 Hydroxypropylcellulose    5 g                                                 Light anhydrous silicic acid                                                                            1 g                                                 Magnesium stearate        1 g                                                 ______________________________________                                    

The above components are blended, granulated and made into 1,000 tabletseach weighing 150 mg by a conventional method. The tablets are furthercoated with hydroxypropyl methylcellulose, talc, titanium dioxode, andsorbitan monooleate in a customary manner. There are obtained 1,000 filmcoated tablets.

EXAMPLE 17

    ______________________________________                                        Capsules                                                                      ______________________________________                                        2-(4-Ethyl-1-piperazinyl)-4-(4-chloro-                                                               20 g                                                   phenyl)quinoline dimaleate                                                    Corn starch            42 g                                                   Lactose                10 g                                                   Microcrystalline cellulose                                                                           25 g                                                   Hydroxypropylcellulose  2 g                                                   Light anhydrous silicic acid                                                                         0.5 g                                                  Magnesium stearate     0.5 g                                                  ______________________________________                                    

The above components are blended, granulated and filled into 1,000capsules by a conventional method.

EXAMPLE 18

    ______________________________________                                        Fine granules                                                                 ______________________________________                                        2-(1-Piperazinyl)-4-(4-chlorophenyl)-                                                                100 g                                                  quinoline maleate                                                             Corn starch            200 g                                                  Lactose                660 g                                                  Light anhydrous silicic acid                                                                          10 g                                                  Hydroxypropylcellulose  30 g                                                  ______________________________________                                    

The above components are blended and made into fine granules by aconventional method. The fine granules are further coated withdimethylaminoethyl acrylatemethacrylate copolymer, macrogol, titaniumdioxide, talc and magnesium stearate in a customary manner.

Industrial Applicability

The compounds of the formula (I) and pharmaceutically acceptable saltsthereof are useful as an antiulcer agent and a therapeutic agent forinflammatory gastrointestinal diseases. They can be used in theprophylaxis and treatment of peptic ulcer and inflammatorygastrointestinal diseases in mammals including human.

What is claimed is:
 1. A method for inhibiting and/or treatment ofpeptic ulcer in mammals which comprises administering to said mammals inneed of such inhibiting and/or treatment an effective amount of acompound selected from the group consisting of2[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)quinoline,2-[4-(3-hydroxypropyl)-1-piperazinyl]-4-(4-fluorophyeny)quinoline,2-(1-piperazinyl)-4-(4-chlorophenyl)quinoline,2-(4-ethyl-1-piperazinyl)-4-(4-chlorophenyl)quinoline,2-[4-(2-hydroxyethyl)-1-piperazinyl]-(4-(4-methylphenyl)quinoline, and2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-trifluoromethylphenyl)quinoline,or a pharmaceutically acceptable salt thereof.
 2. The method accordingto claim 1, wherein said compound is2-[4-(2hydroxyethyl-1-piperazinyl)]-4-(4-fluorophenyl)quinoline, or apharmaceutically acceptable salt thereof.
 3. The method according toclaim 1 wherein said compound is administered in a daily dosage of from0.1 to 20 mg per kg of body weight.
 4. The method according to claim 2,wherein said compound is administered in a daily dosage of from 0.1 to20 mg per kg of body weight.
 5. The method acccording to claim 3,wherein said daily dosage is in the range of from 0.2 to 10 mg per kg ofbody weight.
 6. The method according to claim 4, wherein said dailydosages is in the range of from 0.2 to 10 mg per kg of body weight.